Plasticity of the Streptomyces genome-evolution and engineering of new antibiotics

Streptomyces is a genus of soil dwelling bacteria with the ability to produce natural products that have found widespread use in medicine. Annotation of Streptomyces genome sequences has revealed far more biosynthetic gene clusters than previously imagined, offering exciting possibilities for future combinatorial biosynthesis. Experiments to manipulate modular biosynthetic clusters to create novel chemistries often result in no detectable product or product yield is extremely low. Understanding the coupling between components in these hybrid enzymes will be crucial for efficient synthesis of new compounds. We are using new algebraic approaches to predict protein properties, and homologous recombination to exploit natural evolutionary constraints to generate novel functional enzymes. The methods and techniques developed could easily be adapted to study modular, multi-interacting complex systems where appreciable biochemical and comparative sequence data are available, for example, clinically significant non-ribosomally synthesised peptides and polyketides.